Proprietary: This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shall further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the entire proposal, including, but not limited to the Abstract, Introduction, Specific Aims, Research Plan (all components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract. Chronic low back pain (CLBP) is a leading cause of pain and disability[1-5]. Non-specific low back pain (i.e., without a known cause) is the most pervasive type of back pain [3]. Current therapies [4, 6-12] do not directly address the fact that pain sensation is processed in the brain [4, 6, 7] even though non-specific chronic low back pain (NSCLBP) symptomology can correlate with chronic pain induced changes in brain activity and/or structure [13-21]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of chronic pain in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of chronic pain [14, 15, 22]. However, the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have shown limited, if any, efficacy in treating NSCLBP [23-28]. . It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutic efficacy [29-33]. Electrosonic Stimulation (ESStim?) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat NSCLBP. First in Phase I, to assess the feasibility of the proposed work, we will follow 20 NSCLBP patients after giving a fixed dose of ESStim for 10 days, 20 min/day, over a two-week period (10 SHAM ESStim, 10 ESStim). We will assess a battery of safety, pain, quantitative sensory testing (QST), function, and global psychosocial self-assessments in the patients, evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 40 NSCLBP patients (20 ESStim, 20 SHAM) after giving a fixed dose of stimulation for 10 days, 20 min/day, over a two-week period, followed by three weeks of bi-weekly stimulation, 20 min/day (16 total stimulations). We will evaluate these patients with the same battery of assessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. In parallel with the NSCLBP treatments, we will build MRI derived models of the stimulation fields in the heads (electric and acoustic field models) of the NSCLBP patients to calculate the stimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regression models will then be built and evaluated to predict the NSCLBP patient outcomes related to pain, physical function, and psychosocial assessments as a function of baseline disease characteristics and the MRI based dosing models. The computational work will be combined to develop an optimized NSCLBP ESStim dosing model. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to optimize ESStim for NSCLBP treatment.